Researchers have confirmed a link between thiazolidinediones, particularly pioglitazone, and an elevated risk of bladder cancer in adults with type 2 diabetes. Consequently, pioglitazone should be avoided in selected high-risk patients.

Investigators led by Jeffrey A. Johnson, PhD, Professor of Public Health at the University of Alberta in Edmonton, conducted a meta-analysis to determine the risk of bladder cancer among adults with type 2 diabetes taking this class of diabetes drugs. They found a 22% higher risk of bladder cancer associated with pioglitazone in three cohort studies involving 1.7 million patients. 

The one large randomized, controlled trial, called PROactive (PROspective pioglitAzone Clinical Trial in macroVascular Events), suggests a substantial (236%) increased risk of bladder cancer with pioglitazone, but the low numbers of outcomes produced wide confidence intervals, which were not statistically significant. Rosiglitazone was not associated with a greater risk of bladder cancer in the available studies. Dr. Johnson’s team published their findings in the Canadian Medical Association Journal (2012;184:E685-E683).

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The team concluded that, despite the increased risk, pioglitazone does not have to be avoided in all patients, contrary to the sentiment among regulatory officials in France, who removed the drug from that country’s pharmacy shelves in March 2011 in light of evidence suggesting the medication significantly increases bladder cancer incidence.

Instead, the investigators concur with the warnings issued by the FDA in August 2011 not to use pioglitazone in patients with active bladder cancer and to use caution when prescribing it to those with a prior history of bladder cancer.

“The move to remove pioglitazone in France is probably an over-reaction, given that the risk is only apparent in half the population—men,” Dr. Johnson said. “There are many risks associated with glitazones, which must be balanced with any known benefits. I think that given the considerable attention that has been raised regarding these drugs the clinical community, when aware of the risks, will use the drugs appropriately.”

The team combed the available published and unpublished literature to arrive at a set of five cohort studies, one case-control study, and four randomized controlled trials of thiazolidinediones. They assessed the overall risk of bladder cancer with each member of this class of drugs and with the entire class collectively, taking into account the overall risk of bias in each study.

Five of the studies involving pioglitazone showed an elevated or significantly increased risk of bladder cancer with having ever taken the medication. There was a strong trend toward a significantly increased risk of bladder cancer in the single randomized controlled trial. When the investigators pooled the results of the three cohort studies, which involved a total of 1,739,087 patients, they found a 22% increased risk of bladder cancer associated with the use of pioglitazone.

The researchers observed no association between rosiglitazone and bladder cancer in the one cohort study and two randomized controlled trials that reported rates of bladder cancer among rosiglitazone users.

Overall, in four randomized controlled trials involving the use of any thiazolidinedione, the study demonstrated an elevated risk of bladder cancer but it was not statistically significant. However, the risk was significantly elevated, by 15%, in the five cohort studies.